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Nephrology 19 (2014) 528536

Review Article

Spectrum of renal disease in diabetes

JESSIE TENG,1 KAREN M DWYER,2,3 PRUE HILL,4 EMILY SEE,2 ELIF I EKINCI,3,5,6 GEORGE JERUMS3,5 and
RICHARD J MACISAAC1,3
1
Department of Endocrinology and Diabetes, 2Department of Nephrology and 4Department of Anatomical Pathology, St Vincents Hospital, 3Department of
Medicine, University of Melbourne, 5Endocrine Centre, Austin Health, and 6Menzies School of Health Research, Charles Darwin University, Northern Territory,
Victoria, Australia

KEY WORDS:
AER, diabetic kidney disease, diabetic
nephropathy, eGFR, non-diabetic kidney
disease, renal biopsy.
Correspondence:
Dr Jessie Teng or Dr Richard MacIsaac,
Department of Endocrinology & Diabetes, St
Vincents Hospital, PO Box 2900, Fitzroy, Vic.
3065, Australia. E-mail: jessieth@outlook.com;
r.macisaac@unimelb.edu.au
Accepted for publication 31 May 2014.
Accepted manuscript online 4 June 2014.
doi:10.1111/nep.12288
Disclosure: The authors have no conict of interest to declare.

ABSTRACT:
The spectrum of renal disease in patients with diabetes encompasses both
diabetic kidney disease (including albuminuric and non-albuminuric phenotypes) and non-diabetic kidney disease. Diabetic kidney disease can
manifest as varying degrees of renal insufficiency and albuminuria, with
heterogeneity in histology reported on renal biopsy. For patients with diabetes and proteinuria, the finding of non-diabetic kidney disease alone or
superimposed on the changes of diabetic nephropathy is increasingly
reported. It is important to identify non-diabetic kidney disease as some
forms are treatable, sometimes leading to remission. Clinical indications for
a heightened suspicion of non-diabetic kidney disease and hence consideration for renal biopsy in patients with diabetes and nephropathy include
absence of diabetic retinopathy, short duration of diabetes, atypical chronology, presence of haematuria or other systemic disease, and the nephrotic
syndrome.

SUMMARY AT A GLANCE
This review article highlights the
heterogeneity of renal disease in patients
with diabetes. The spectrum of renal
disease in patients with diabetes
encompasses both diabetic kidney disease
(including albuminuric and non-albuminuric
phenotypes) and non-diabetic kidney
disease which can be independent or
superimposed on albuminuric diabetic
kidney disease. It is important to
identifying non-diabetic kidney disease
because it is potentially reversible. The
clinical features suggestive of non-diabetic
kidney disease, which should prompt
consideration of renal biopsy, are
discussed.

The global burden of diabetes is increasing, with the largest

increase in prevalence estimated to occur in the Middle East,
Sub-Saharan Africa and India.1 This increase is principally
attributable to a rapid rise in cases of type 2 diabetes (T2DM),
driven by a combination of obesity, urbanization and an
ageing population. As such, the public health impact of
diabetes-related complications is enormous, and is no better
528

exemplified than by the rapid increase in chronic kidney

disease (CKD) in people with diabetes. It is now welldocumented that diabetes is the leading cause of end-stage
renal disease (ESRD) in the world.2
The current clinical classification of CKD, regardless of
aetiology, is based on estimated glomerular filtration rate
(eGFR) and albumin excretion rate (AER),3,4 recognizing the
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Renal disease in diabetes

Box 1 Clinical Case Vignettes

Case 1. DKD in T1DM
A 47-year-old man was diagnosed with T1DM since childhood, with multiple complications including proliferative
retinopathy, peripheral neuropathy and cerebrovascular disease. Other medical history included obesity and hypertension;
there was no family history of renal disease. He presented with worsening nephrotic-range proteinuria (24 h urinary
protein 6.5 g) and rapid deterioration in renal function; HbA1C was 9.8%. Renal biopsy confirmed Class IV DN (Fig. 1).
Case 2. DKD in T2DM
A 38-year-old obese woman presented with rapid weight gain (12 kg in one week) associated with bilateral oedema to her
upper thighs. She had significant proteinuria (urinary protein/creatinine ratio 378 mg/mol) with impaired renal function
(serum creatinine 122 mol/L). Past history was notable for gestational diabetes. She was diagnosed with T2DM (HbA1c
13.4%) and renal biopsy confirmed Class III DN with nodular glomerulosclerosis (Fig. 2).
Case 3. FSGS causing nephrotic syndrome
A 43-year-old obese woman with 11 year history of T2DM, presented with nephrotic syndrome (gross peripheral oedema,
urinary protein/creatinine 913 mg/mol, serum albumin 26 g/L) and preserved renal function (eGFR 77 mL/min). Her
HbA1c was 7% with no known diabetic complications. Renal biopsy demonstrated FSGS with mild chronic
tubulointerstitial damage (Fig. 4).
Case 4. Hypertensive kidney disease
A 74-year-old man with T2DM for 7 years was referred with gradually worsening renal impairment (eGFR 21 mL/min).
His HbA1C was 6.3% on oral agents with no vascular complications. Other medical history included hypertension and
obstructive sleep apnoea. Urine sediment did not show any proteinuria; kidneys were small-sized on ultrasonography.
Renal biopsy revealed hypertensive nephrosclerosis (Fig. 5).
Case 5. IgA nephropathy
A 50-year-old man presented with significant proteinuria, 5 years post diagnosis of T2DM. His medical history included
obesity, hypertension and hyperlipidaemia. Urinary protein excretion was 11 g/day, with normal eGFR and active urinary
sediment. HbA1C was 8%. Renal biopsy showed features of mesangial proliferative IgA nephropathy with chronic
tubulointerstitial damage and nephrosclerosis (Fig. 6).
Case 6. Membranous nephropathy and anti-GBM disease7
A 22-year-old male with T1DM presented with nephrotic syndrome (urinary protein excretion 14 g/day, serum albumin
23 g/L), acute kidney injury (serum creatinine 387 mol/L) and active urinary sediment (>1000 106/L dysmorphic
erythrocytes). Renal biopsy showed focal segmental necrotizing glomerulonephritis on a background of moderate nodular
mesangial expansion and hypercellularity with several showing KimmelstielWilson nodules (Fig. 7). Immunofluorescence
showed strong linear GBM staining for IgG. Electron microscopy showed Stage 1 membranous nephropathy with small
subepithelial electron dense immune-type deposits with GBM membrane spike formation.

relationship between these two factors and adverse

outcomes. This has resulted in a broadening spectrum of
clinical presentations for diabetic kidney disease (DKD),
with the phenotype of non-albuminuric CKD being increasingly recognized. The term diabetic nephropathy (DN)
should therefore now only be reserved for patients with
persistent clinically detectable proteinuria that is usually
associated with an elevation in blood pressure and a
decline in eGFR. However, the finding of subclinical proteinuria or microalbuminuria is sometimes referred to as
incipient DN.5
There is also increasing awareness of the heterogeneity of
renal biopsy findings in people with diabetes. Most patients
with type 1 diabetes (T1DM) and reduced eGFR have classic
glomerular changes of DN regardless of albuminuria status.
Typical renal structural changes of DN are usually also
observed in patients with T2DM, reduced eGFR and albumi 2014 Asian Pacic Society of Nephrology

nuria. However, predominantly interstitial, tubular or vascular damage or near normal renal structure have also been
reported in biopsies obtained from patients with T2DM,
regardless of eGFR or albuminuria status, in the absence of
any other known cause for renal dysfunction. Despite the
above, in people with diabetes and proteinuria, non-diabetic
kidney disease (NDKD) alone or superimposed on DN
changes is not an uncommon finding.6
It is important that NDKD is diagnosed. Despite the attention to strict metabolic control and blockade of the renin
angiotensin-aldosterone system, proteinuric DKD is usually
progressive, whereas NDKD is potentially treatable, depending on aetiology. Therefore, we have briefly reviewed the
contemporary spectrum of DKD, the histology and clinical
predictors of NDKD and present several clinical vignettes
(Box 1) to illustrate the variability of renal disease in diabetic
patients that have presented to one of our hospitals.
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J Teng et al.

DIABETIC KIDNEY DISEASE

The earliest clinical evidence of classical DKD is the appearance of microalbuminuria ( 30 mg/day or 20 g/min).
Without specific interventions, up to 80% of T1DM patients
with sustained microalbuminuria develop overt proteinuria
(300 mg/day or 200 g/min) over 1015 years.810 ESRD
develops in 50% of T1DM patients with overt proteinuria
within 10 years and in >75% by 20 years. A higher proportion of T2DM individuals are found to have established proteinuria at the time of diagnosis of their diabetes due to the
delay in the diagnosis of diabetes. Without specific interventions, up to 40% of T2DM patients with microalbuminuria
progress to overt nephropathy, but by 20 years after onset of
overt nephropathy, only approximately 20% will progress to
ESRD.11
The exact reasons why an individual with diabetes will
progress to develop DKD and then subsequently develop
ESRD still remain to be fully defined. Despite this, there is
most likely a strong genetic determinant for the risk of developing DKD and ESRD. Indeed, recent genomic-wide linkage
studies have described the localization of quantitative trait
loci that influence GFR in diabetes.12,13 These findings may
help to further elucidate the genetic susceptibility to the
development of advanced DKD.

HISTOPATHOLOGY OF DKD
The spectrum of histologic changes seen in DKD is variable. In
2010, a new pathological classification of DKD was proposed
for patients with diabetes,14 based on glomerular features:
1 Class I: Glomerular basement membrane (GBM) thickening, diagnosed by transmission electron microscopy.
2 Class II: Mesangial expansion A: mild; B: severe.
3 Class III: Nodular glomerulosclerosis (KimmelstielWilson
lesion).
4 Class IV: Advanced diabetic glomerulosclerosis (>50%
global glomerulosclerosis).
The most characteristic lesion seen in patients with T1DM
and DN is nodular glomerulosclerosis.15 Other typical lesions
include hyalinosis of afferent and efferent arterioles,
glomerular capsular drops, diffuse glomerular lesions with
capillary wall thickening and mesangial matrix expansion
(Case 1, Fig. 1).
Renal histology in patients with T2DM is also markedly
heterogeneous (Case 2, Fig. 2). A study of T2DM patients
with normal eGFR and microalbuminuria by Fioretto et al.
categorized renal biopsy findings into three patterns:
1 29% had normal or near normal renal structure Fioretto
class 1 (C1).
2 29% had typical DN with predominant glomerular
changes Fioretto Class 2 (C2).
3 41% had atypical patterns with mild glomerular diabetic
changes and disproportionately severe tubular, interstitial or
vascular damage Fioretto Class 3 (C3).16
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Fig. 1 Case 1: Class IV DN. (A) >50% of glomeruli are globally sclerosed. (B)
Preserved glomeruli show severe mesangial expansion.

The reasons for different kidney reactions to glycaemic

injury are unclear, although potential factors include degree
and duration of metabolic control, co-existing hypertension,
interlobar renal vascular changes and presence of diabetic
retinopathy as a marker of microvascular damage.17

NORMOALBUMINURIC DKD
Recently, a new DKD phenotype has been described in diabetic patients with low GFR in the absence of microalbuminuria.5 Approximately 25% of patients with T1DM or
T2DM have been reported to develop normoalbuminuric
CKD.1820 Distinct sets of risk factors have been described for
the development of low eGFR or increased AER, suggesting
that eGFR and AER are complementary rather than obligatory
markers of DKD.5 Some studies that have attempted to document the natural history of normoalbuminuric DKD suggest a
relatively benign course compared with albuminuric DKD,
with lower rates of dialysis and mortality,21,22 whilst others
have reported similar rates of decline in renal function.20
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Renal disease in diabetes

patients with normoalbuminuria and preserved eGFR.25

However, compared with patients with microalbuminuria or
macroalbuminuria and CKD, the typical glomerular changes
of DKD were less common in patients with normoalbuminuric CKD.26
The above suggests that renal structural changes are more
heterogeneous in normoalbuminuric than in albuminuric
CKD (Fig. 3). In particular, for patients with T2DM and low
eGFR, a recent biopsy study of 32 patients reported typical
Fioretto C2 classification typical DN changes for 22/23
microalbuminuric or macroalbuminuric patients with only
1/23 being classified as C3 atypical patterns of renal injury.
For the patients with normoalbuminuria and low GFR, 2/8
had C1- near normal biopsy findings, 3/8 had C2 typical
DN changes and 3/8 had C3 atypical patterns of renal
damage. In contrast, as mentioned above, a similar proportion of C1, C2 and C3 changes have been reported in renal
biopsies from patients with T2DM, microalbuminuria and
preserved renal function.16,26
In summary, glomerular or non-glomerular renal structural changes in T2DM are more heterogenous in
normoalbuminuric than in albuminuric renal insufficiency.
This implies that age, blood pressure and intra-renal vascular
disease may contribute to decreases in renal function independently of changes in albuminuria.

NON-DIABETIC KIDNEY DISEASE

Fig. 2 Case 2: Class III DN. (A) This glomerulus shows severe mesangial expansion with KimmelstielWilson nodule (arrow). (B) Both afferent and efferent
arterioles show marked arteriolar hyalinosis (asterisks).

Renal biopsies of normoalbuminuric T1DM patients with

preserved eGFR showed that greater width of the GBM predicted progression of DKD.23 Moreover, normoalbuminuric
T1DM patients with reduced eGFR had more advanced
glomerular lesions compared with patients with preserved
renal function.24 Similarly, in T2DM, patients with
normoalbuminuric CKD (eGFR <60 mL/min per 1.73 m2)
were found to have more advanced glomerular,
tubulointerstitial and vascular lesions compared with
2014 Asian Pacic Society of Nephrology

NDKD can either be independent of, or superimposed on,

DN. Glomerular causes of NDKD include immunoglobulin A
(IgA) nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, acute interstitial nephritis
(AIN), hypertensive renal disease, focal segmental
glomerulosclerosis (FSGS) and crescentic glomerulonephritis
due to ANCA-associated disease and anti-glomerular basement membrane (anti-GBM) glomerulonephritis (Cases 36,
Figs 47).
The prevalence and type of NDKD in patients with diabetes
reported in the literature is highly variable (Table 1). This
disparity reflects different selection criteria and study design,
reporting bias, threshold for biopsy, and geographical and
ethnic differences. Mazzucco et al. highlighted the impact of
different biopsy criteria on reported prevalence of NDKD.40
They showed that although patients were recruited from an
ethnically homogenous population belonging to the same
geographic area, centres with unrestricted biopsy policies
reported 50% of patients having DKD alone, with the
remainder having features of mixed DKD and NDKD;
whereas centres with restricted biopsy policies had lower
rates of DKD and the majority of NDKD was not associated
with DKD.
Further complicating the diagnosis of NDKD in diabetic
patients is the overlap in histology findings of mild glomerulonephritis with early DKD changes.41 Features of minimal
change disease under light microscopy may appear similar to
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J Teng et al.

Fig. 3 Histological spectrum of renal biopsy ndings seen in patients with low eGFR and normoalbuminuria. (A) Normal glomerulus and arteries. (B) Advanced
diabetic glomerulosclerosis and arteriosclerosis (inset). (C) Minimal glomerular mesangial expansion and severe arteriosclerosis (inset). All images periodic
acidSchiff stain, original magnication 200 (reproduced with permission from Ekinci et al.26).

Fig. 5 Case 4: Hypertensive nephrosclerosis. Of three glomeruli, one is

sclerosed, one shows ischemic change (arrow) and the other no evidence of
DN.
Fig. 4 Case 3: FSGS. Glomerulus with segmental sclerosis (arrow). Other glomeruli showed no evidence of DN.

Class I DN. Hence, electron microscopy is important in renal

biopsy assessment in diabetes.

CLINICAL PREDICTORS OF NDKD

Given the prevalence of NDKD and the potential for treatment, it is important to identify clinical predictive factors of
NDKD in diabetic patients and perform a renal biopsy to
532

confirm diagnosis. Recently, several retrospective studies

have reported clinical parameters to differentiate DKD from
NDKD.
The presence of diabetic retinopathy (DR) prior to renal
biopsy is strongly associated with DKD.35,37,38,42,43 In one
study analysing 110 renal biopsies of patients with T2DM,
the presence of DR was highly predictive of DKD (sensitivity
84%, specificity 63%).38 In contrast, up to 70% of diabetic
patients without retinopathy, but with albuminuria may
have DKD,44 suggesting that whilst the absence of DR is a
strong predictor of NDKD, it cannot exclude DKD. A recent
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Renal disease in diabetes

Fig. 6 Case 5: IgA nephropathy. (A) Glomerulus with mild mesangial

hypercellularity but no evidence of DN. (B) Immunoperoxidase stain shows
strong granular mesangial staining for IgA.

analysis of the Diabetes Control and Complications Trial

(DCCT) which involved participants with T1DM, found DR
and DKD to be risk factors for development and progression
of the other, independent of other established microvascular
risk factors, suggesting a shared aetiological basis.45 However,
up to 25% of patients had discordant DR progression and DN
development, which would argue for a partly different
pathological mechanism.45 Furthermore, an analysis of Asian
patients with diabetes suggests that DR is only associated
with albuminuric DKD, and not normoalbuminuric DKD.46
Duration of diabetes is a significant predictive factor for
NDKD. Given the natural history of DN, the onset of proteinuria less than five years from onset of T1DM would be
suggestive of another disease process. Studies of T2DM
patients have found that diabetes >10 years duration was
2014 Asian Pacic Society of Nephrology

associated with a higher likelihood of DKD.6,38 Conversely,

Tone et al. showed that duration of T2DM <5 years was
highly sensitive (75%) and specific (70%) for NDKD.35
Chang et al. also reported a mean diabetes duration of 5.9
years in patients with NDKD versus 10.6 years in patients
with DKD alone (P < 0.001).47 However in T2DM patients
without DR, there appears to be no difference in duration of
diabetes in those who developed DKD or NDKD.44
A recent meta-analysis by Liang et al. also identified
absence of DR and shorter duration of diabetes as significant
predictors of NDKD in patients with T2DM.48 Their results
suggested lower HbA1C, lower blood pressure and the presence of haematuria to be potentially helpful in distinguishing
NDKD, although heterogeneity between the studies prevented more definitive conclusions.
The relevance of microscopic haematuria in predicting
NDKD remains controversial, partly due to varying definitions of haematuria. Some studies recognize the importance
of microscopic haematuria in distinguishing NDKD (sensitivity 80%, specificity 57%);38 others have found it less discriminative.35,42 Moreover, microscopic haematuria may be a
feature of T2DM patients with biopsy-proven DKD and overt
proteinuria.34 A study involving patients with biopsy-proven
DKD and overt proteinuria, found an association between
persistent haematuria and arteriolar hyalinosis, but this did
not provide prognostic clinical significance.49 On the other
hand, urinary acanthocytes are reported to have high specificity for glomerular NDKD (100%), but low sensitivity.43,50
The occurrence of acute renal failure also has high specificity
(97%) but poor sensitivity (45%) in predicting NDKD.38
Although nephrotic-range proteinuria is common in DKD,
nephrotic syndrome with gross oedema and low albumin
levels is uncommon, and should prompt renal biopsy.
Clinical findings of systemic illness are useful in predicting
NDKD. Purpura and arthralgia may suggest Henoch
Schonlein purpura often associated with IgA nephropathy,
whereas precedent infection is a strong indicator of acute
post-streptococcal glomerulonephritis.
In terms of serologic abnormalities, positive ANA titres
were not helpful in differentiating between DKD and
NDKD.6,43 Some studies have found positive ANCA titres
highly specific for pauci-immune glomerulonephritis;43
others found no difference in ANCA positivity between DKD
and NDKD.6
The absence of peripheral neuropathy is not useful in
predicting NDKD. One study found that neuropathy
occurred in <10% of diabetic patients with renal impairment,
although the absence of neuropathy may have impacted on
the initial decision for renal biopsy.42

CLINICAL INDICATIONS FOR RENAL BIOPSY

The routine presumption that DKD is the cause of renal
impairment in diabetic patients may be inaccurate; however,
the threshold for renal biopsy varies amongst nephrologists.
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J Teng et al.

Fig. 7 Case 6: Membranous nephropathy and anti-GBM disease. (A) Glomerulus with segmental necrosis (arrow) and cellular crescent (asterisk). (B) Glomerulus
with class III DN with KimmelstielWilson nodule (arrow). (C) Strong linear GBM staining for IgG characteristic of anti-GBM GN. Inset shows dual pattern of GBM
staining, both granular and linear, on confocal microscopy. (D) Electron microscopy shows GBM thickening and small subepithelial electron dense deposits
characteristic of early membranous nephropathy.

Biesenbach et al. argued that for T2DM patients fulfilling

the clinical criteria for DKD (proteinuria, normal urinary
sediment, normal kidney size and diabetes duration >10
years), and vascular nephropathy (normal urine status,
normal or near normal protein excretion, shrinkage of
kidney, renal artery stenosis on ultrasonography), routine
renal biopsy is not required.51 Others advocate more extensive use of renal biopsies, given that NDKD is not easily
predictable based on clinical and laboratory findings.40,44
Even in the presence of diabetic retinopathy, prediction of
DKD based on clinical course of disease and laboratory findings had only 65% sensitivity and 76% specificity.43
We suggest that renal biopsy be considered in diabetic
patients with CKD (eGFR <60 mL/min per 1.73 m2) and the
following features:
Absence of DR
Short duration of diabetes (<5 years)
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Absence of typical chronology, e.g. acute onset of proteinuria, progressive decline in renal function
Presence of haematuria
Presence of other systemic disease
Nephrotic syndrome
SUMMARY
There is significant heterogeneity in the spectrum of renal
disease seen in patients with diabetes. Although DKD is a
common cause of chronic kidney disease in patients with
diabetes, exclusion of NDKD is important because many
forms of NDKD are potentially treatable and reversible.
Renal biopsy should be considered in a carefully selected
population where the disease course is atypical and clinical
suspicion of NDKD is high. Absence of retinopathy and short
duration of diabetes are the strongest predictors of NDKD.
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Renal disease in diabetes

Table 1 Prevalence and type of NDKD in some studies from the Asia-Pacic region reported in the literature
Country

China
China (Hong Kong)
China (Hong Kong)
China (Hunan)
China (Shanghai)
India
India
Japan
Japan
Korea
Korea
Malaysia
Pakistan

Type of
diabetes

Number of
cases

Duration of
study (years)

NDKD
prevalence

Most common NDKD

Study

T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM
T2DM

244
68
51
220
69
18
160
50
97
110
126
110
68

9
14
2
10
5
NA
5
16
NA
2
8
4
4

7.8%
65%
33.3%
45.5%
52.2%
50%
72.5%
30%
63.9%
62.7%
60.3%
37.3%
69%

IgA nephropathy
IgA nephropathy
IgA nephropathy
IgA nephropathy
FSGS
Membranous nephropathy
AIN
Membranous nephropathy
IgA nephropathy
IgA nephropathy
IgA nephropathy
AIN
AIN

Zhuo et al.27
Wong et al.28
Mak et al.29
Bi et al.30
Mou et al.31
Premalatha et al.32
Soni et al.33
Akimoto et al.34
Tone et al.35
Byun et al.36
Oh et al.37
Chong et al.38
Yaqub et al.39

Including mixed DN and NDKD. NA, not available; DN, diabetic nephropathy; NDKD, non-diabetic kidney disease; T2DM, type 2 diabetes. AIN, acute interstitial
nephritis; FSGD, focal segmental glomerulosclerosis.

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2014 Asian Pacic Society of Nephrology